The present invention pertains to combination radiotherapy of tumors and more specifically to pharmaceutical compositions, and methods of treatment by gene therapy designed to sensitize tumors in animals, notably humans, and render them more susceptible to radiation, thus significantly reducing the amount of radiation required to kill neoplastic cells while at the same time making the radiation far more tissue specific to the tumor site.
The limited ability of anti-neoplastic therapy to distinguish neoplastic from normal cells on the basis of proliferative behavior has inspired a search for biochemical characteristics of neoplastic cells that are tumor specific rather than proliferation specific. Unfortunately current molecular genetic studies have failed to support the expectation that such characteristics are a consistent feature of neoplastic cells. Rather these studies suggest that the neoplastic state can be explained without postulating tumor specific functions, but merely the operation of normal proliferation-specific functions at abnormal levels, as a result of changes (sometimes minimal) in the structure of growth-regulatory genes or changes in their number or chromosomal environment. This conclusion suggests that a continued search for highly specific attributes of neoplastic cells cannot be relied upon for a general solution to the problems of cancer therapy. Major reductions in the lethality of cancer will require alternative approaches that do not depend on the natural occurrence of such attributes.
One alternative strategy entails the artificial creation of differences between normal and neoplastic cells through prophylactic use of gene insertion techniques. In other words, manufacturing biochemical differences which can be exploited to systematically and specifically target neoplastic cells for destruction. This invention involves combination gene therapy and radiation treatment to inhibit proliferation and kill neoplastic cells. Gene insertion protocols are used to artificially manufacture biochemical differences in target tumor cells which are then exploited to sensitize the cells to the effects of radiation.
Thus an object of the present invention is to provide therapeutic materials and procedures for treating tumors using, for example, ultraviolet light, near visible light (313 nm), x, gamma, xcex2, xcfx80meson, neutron, or other radiation entities.
Another object of the invention is to sensitize tumor cells to radiation using gene therapy to engineer biochemical differences in tumor cells which are exploited to confer sensitivity to the effects of radiation therapy.
This invention pertains generally to the introduction of genes to tumor cells to modify a drug that acts as a radiosensitizer. In one embodiment, it is postulated that certain CMV or thymidine kinase-activated nucleoside analogues derived from either purine or pyrimidine building blocks, can be potent radiation sensitizers to transformned mammalian cells, such that the addition of radiation therapy may provide an additive or synergistic benefit. The viral thymidine kinase allows activation of drugs (e.g. pyrimidine nucleoside analogs) which are not (or poorly) activated in cells containing cellular thymidine or deoxycytidine kinase. This allows for selective radiosensitization of cells containing viral thymidine kinase by gene manipulation when certain analogs which are precursors to radiosensitizers are utilized.
Applicant""s invention represents the first demonstration of selective enhancement of radiation sensitivity by proliferating cancer cells using a gene therapy approach. The selective cytotoxicity of the antiviral drug ganciclovir on tumor tissue has been demonstrated previously, but it would be extremely difficult to achieve a complete erradication of locally advanced tumors with the antiviral drug alone. According to the present invention, further selective cytotoxicity can be achieved with the addition of radiation and the use of agents which are not merely antiviral agents, but those which are precursors to true radiosensitizers.